There is a fundamental knowledge gap in understanding how precise functional neuronal circuits form in the neocortex, which is the most complex part of the brain and controls all aspects of behavior, from perception to emotion and cognition. The continuing existence of this gap represents a major problem because it severely hinders the understanding of malformation and malfunction of the neocortex. The long-term goal is to better understand the assembly of precise neuronal circuits in the developing neocortex. The objective in this particular application is to investigate the origin, basis and regulation of precise electrical synapse formation between neocortical excitatory neurons. The central hypothesis is that the lineage relationship guides precise electrical synapse formation between excitatory neurons in the developing neocortex. This hypothesis has been formulated on the basis of strong preliminary data produced in the applicant's laboratory. The rationale for the proposed research is that the processes of neurogenesis and neuronal migration regulate the formation of specific electrical synapses between excitatory neurons in the developing neocortex. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) to uncover the mechanisms that control the specificity of strong electrical synapse formation between sister excitatory neurons; 2) to determine the mechanisms that regulate the developmental removal of electrical synapses between sister excitatory neurons; and 3) to investigate the mechanisms that drive the preferential development of specific chemical synapses between electrically coupled sister excitatory neruons. The approach is innovative, because it combines a number of cutting-edge techniques including retroviral engineering, in utero labeling, mouse genetics, quadruple whole-cell patch clamp recording and two photon/confocal laser scanning microscopy. The proposed research is significant, because it is expected to fundamentally advance the understanding of precise neuronal circuit assembly and functional development of the neocortex. Ultimately, such knowledge has the potential to inform early diagnoses and the development of therapeutic treatments for many devastating brain disorders including schizophrenia, epilepsy, mental retardation and autism.